This project aims to differentiate between neural mechanisms that underlie placebo analgesia. Currently, many researchers have concluded that placebo analgesia depends primarily on an individual's belief in a treatment, but alternative evidence suggests that other lower level processes may be involved in analgesia that are dissociable from belief. In the proposed study, belief in a placebo treatment will be manipulated using verbal information within subjects, and both experience and belief will be manipulated using conditioning between subjects. The proposed study will separate the effect of verbal information on placebo analgesia from implicit values learned through experience. Subjects are conditioned to believe that a placebo treatment is effective at reducing pain by first receiving a series of high-temperature painful stimulations, and then receiving a second series of low- temperature painful stimuli after the experimenter applies a placebo cream with instructions that it will reduce pain. Half of the subjects will experience a single conditioning session (short conditioning group), and the other half will have four separate sessions on different days (long conditioning group). For all subjects, the placebo effect will be tested in the scanner after the final conditioning session. During testing, subjects will rate the painfulness of medium-temperature painful stimuli with and without the placebo cream. Subjects will then be informed that the treatment they received was a placebo, and will be asked to again rate the painfulness of medium-temperature painful stimuli with and without the placebo cream. Revealing the nature of the treatment allows comparison of fMRI based pain activity at different levels of belief, and allows comparison across groups of subjects depending on how much conditioning they received. FMRI analysis for this project will focus on dissociating the effects of verbal information and experience among pain related brain regions, and whether the relationship between brain activation, pain, and the belief in a treatment is different depending on the amount of training received. We anticipate that pain-related activity in frontal pain areas, including the orbitofrontal and anterior cingulate cortices, will depend on belief in the treatment and that pain-related activity in lower order areas, such as the periaqueductal gray and rostroventromedial medulla, will depend on the amount of conditioning subjects receive. We will use classification techniques to predict which subjects will continue to experience placebo analgesia after the placebo treatment is revealed. We expect to find that activation in the lower order pain regions predicts whether subjects continue to experience placebo analgesia after the reveal. This research will provide a new way of thinking about analgesia and pain relief. If multiple pathways for placebo analgesia are found, it would suggest novel treatments and methods for improving existing pain relief treatments using conditioning to assist the natural pain relief system in the body. PUBLIC HEALTH RELEVANCE: This project will examine differences in brain systems governing pain relief. This study will focus on brain regions involved in pain relief, testing whether activity in specific regions predicts the effectiveness of a placebo treatment. The results of this study may suggest various procedures to use placebos to give people pain relief, even if they know the treatment is a placebo.